Antiprotozoal Compounds

ABSTRACT

The invention is directed to a compound of formula I, as defined herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical composition containing a compound of formula I, a method of treatment of a disorder or condition that may be treated by administration of the compound, the method comprising administering to a mammal in need of such treatment a compound of formula I as described above, and a method of treatment of a disorder or condition selected from the group consisting of Human African Trypanosomiasis (HAT), Chagas disease, Leishmaniasis and malaria, the method comprising administering to a mammal, including a human, in need of such treatment a compound of formula I as described above.

This application claims the benefit of U.S. Provisional application Ser.No. 61/697,799 filed on Sep. 6, 2013.

BACKGROUND OF THE INVENTION

This invention is directed to compounds of the formula I describedherein, to a pharmaceutical composition comprising such compounds and tomethods of preventing or treating disorders or conditions that may betreated by administration of such compounds to a mammal in need,including humans. In particular, the compounds of the current inventionare potentially useful for treating certain protozoal infectionsincluding, for example, human African trypanosomiasis (HAT) and Chagasdisease.

Human African Trypanosomiasis (HAT) is a disease spread by a parasiticorganism, trypanosoma brucei, which is transmitted to humans primarilyvia bites from the tsetse fly—transmission may also occur via bloodtransfusion or in utero exposure of a fetus from an infected mother viathe placenta. It is often referred to as “sleeping sickness” because ofthe symptoms that develop in patients who have progressed to theadvanced, or Stage 2, level of infection wherein the parasite has passedthe blood brain barrier (BBB) exposing the central nervous system (CNS)of the victim to further infection by the parasite. Left untreated, thislatter stage of the disease is typically fatal. Jacobs and Ding, AnnualReports in Medicinal Chemistry, (2010) 45, 277-294; Rollo, Chapter 50 ofGoodman and Gilman's, The Pharmacological Basis of Therapeutics, 12^(th)Ed., (2011), 1419-1441.

The disease is found in two forms, depending on the parasite sub-speciesinvolved, either Trypanosoma brucei gambiense or Trypanosoma bruceirhodesiense. Humans are the primary host for Trypanosoma bruceigambiense, whereas wild game animals and cattle are the primary targetof T. b. rhodesiense. T. b. gambiense is found in central and westernAfrica and causes a chronic condition that can remain in a passive phasefor months or years before symptoms emerge. T. b. rhodesiense is foundin southern and eastern Africa; symptoms of infection by T. b.rhodesiense generally emerge in a few weeks and are more virulent andfaster developing than T. b. gambiense.

While approximately one-half million inhabitants of sub-Saharan Africaare potentially infected each year by the hemolymphatic, Stage 1, formof HAT. The number of HAT cases has been diminishing, with the WHOestimating an annual mortality of 10,000 (see P. P. Simarro, et al,International Journal of Health Geographics, 2010, 9, 57). However, thistrend has varied over the years and, with few efficacious and costeffective preventative measures being consistently used, the number ofcases would quickly rebound. Symptoms include fever, headaches, jointpains and itching, as well as severe swelling of lymph nodes.Chronically, HAT can produce more extensive symptoms including anemia,endocrine, cardiac and kidney dysfunctions.

The drugs that are available act directly on the invasive protozoa inthe bloodstream; penetration of the blood-brain barrier (BBB) haslimited the use of some of these drugs to treatment of thehemolymphatic, first stage of HAT. These include suramin, developed inthe 1920's and primarily used for Stage 1 T. b. rhodesiense HAT;pentamidine, discovered in 1940, which requires multiple intramuscular(i.m.) injections and is only effective for Stage 1 HAT; melarsoprol(identified in 1949) which also requires multiple, painful dailyinjections and is highly toxic, often used for the most severely illStage 2 patients; and eflornithine, a drug developed in 1981 whichrequires slow i.v. infusions over a two-week period to ensure sufficientCNS exposure to treat T. b. gambiense-induced Stage 2 HAT. Anifurtimox-eflornithine combination therapy (NECT) was created in 2009;it appears to be better tolerated for Stage 2 HAT patients (see Nok,Expert Opinion in Pharmacotherapy, 2005, 6(15), 2645-2653).

Of growing concern in recent years is the issue of cross-resistance tosome of these medications. This has been observed with pentamidine andarsenicals like melarsoprol. (See de Koning, Trends in Parasitology,(2008) 24(8), 345-349).

Interestingly, the organism that is responsible for HAT, T. brucei, isrelated to other parasitic species that can cause severely debilitatingdiseases in humans and animals. Chagas disease, caused by the relatedparasite T. cruzi, is prevalent in South America, affecting up to 10million individuals and has also been detected in cattle; fatalitiesfrom Chagas are estimated to be about 21,000 per year. Leishmaniases, intheir various manifestations—cutaneous Leishmaniasis (via L. major, L.mexicana, L. aethiopica, L. tropica), mucocutaneous leishmaniasis (L.braziliensis) and visceral leishmaniasis (L. donovani/infantum) areestimated to affect nearly 2 million people on four continents. It isquite possible that any new treatment for HAT which targets the T.brucei parasite could have sufficient efficacy against these relatedparasitic species and, therefore would be a valuable improvement inantiparasitic therapy. (See Silva, et al, Biochemical Pharmacology,(2007) 73, 1939-1946).

One of the most commonly used HAT treatments for Stage 1 is pentamidine.This diamidine compound has been extensively studied with respect tostructure-activity relative to the replacement of its 1,5-dioxopentylsection by a variety of aryl and heteroaryl rings (See, e.g., R. R.Tidwell, et al, in Journal of Medicinal Chemistry, 2006, 49, 5324;Journal of Medicinal Chemistry, 2007, 50, 2468; Journal of MedicinalChemistry, 2008, 51, 6923; Journal of Medicinal Chemistry, 2009, 52,5763; Journal of Medicinal Chemistry, 2010, 53, 254). Little researchhas been done to enhance pentamidine's brain concentration through theincorporation into the molecule of CNS-penetration enhancing groups,such as those found in some effective antipsychotic and antidepressantdrugs currently on the market.

Aromatic amidine compounds have been reported to have efficacy in thetreatment of human and animal disorders like giardiasis (U.S. Pat. No.4,963,589, issued Oct. 16, 1990), pneumocystis carinii pneumonia (U.S.Pat. No. 4,933,347, issued Jun. 12, 1990), leishmania donovani (U.S.Pat. No. 5,786,383, issued Jul. 28, 1998), plasmodium falciparum malaria(U.S. Pat. No. 5,206,236, issued Apr. 27, 1993), as well as their use asanticoagulants (U.S. Pat. No. 5,866,577, issued Feb. 2, 1999),antiproliferative agents (U.S. Pat. No. 6,699,862, issued Mar. 2, 2004)and antihistamine substances (U.S. Pat. No. 4,748,165, issued May 31,1988)

SUMMARY OF THE INVENTION

This invention is directed to compounds of the formula I:

or the pharmaceutically acceptable salt(s) thereof, wherein:

X₁ is a group of the general formula:

wherein R5, R6 and R7 are independently defined as H, C₁-C₆ alkyl,C₃-C₇-cycloalkyl, -(un)substituted aryl, or heteroaryl; or

X₁ is a heteroaryl ring, including, for example, 2-imidazolyl,4-imidazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl,4-oxazolyl, 5-oxazolyl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-2-yl,1,2,4-thiadiazol-4-yl, 1,2,3-triazolyl-2-yl, 1,2,3-triazol-1-yl,1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl,1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,2,3,4-tetrazol-5-yl,1,2,3,4-tetrazol-1-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-2-yl,1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3-pyrimidin-2-yl,1,2-pyrazin-3-yl, 1,2,4-triazin-3-yl;

R5 and R6, taken together with the N—C═N group to which they areattached form a 5-10 member cyclic or bicyclic ring, optionallysubstituted with up to two additional heteroatoms selected from thegroup consisting of N, O or S (including, for example, the cyclic orbicyclic rings imidazole, oxadiazole, thiadiazole, benzimidazole) andoptionally substituted with H, C₁-C₆ alkyl or cycloalkyl groups,(un)substituted aryl or heteroaryl rings, or oxygen, e.g., sulfoxide orsulfone); or

R6 and R7, taken together with the nitrogen atom to which they areattached form a 5-10 member cyclic or bicyclic ring, optionallysubstituted with up to two additional heteroatoms selected from thegroup consisting of N, O or S (including, for example, the cyclic orbicyclic rings azetidine, pyrrolidine, piperidine, azepine, piperazine,morpholine, thiomorpholine) and optionally substituted with H, C₁-C₆alkyl or cycloalkyl groups, aryl or heteroaryl rings, or oxygen, e.g.,sulfoxide or sulfone);

X₂ is H, Cl, or F;

R1 and R2 are independently hydrogen or methyl;

R3 is hydrogen; and

n is zero, one or two.

The invention is also directed to a pharmaceutical composition fortreating, for example, a disorder or condition (e.g., human Africantrypanosomiasis, Chagas disease) in a mammal, including a human, thatmay be treated by administering to a mammal in need of such treatment acompound of formula I as described above, or a pharmaceuticallyacceptable salt thereof, that is effective in treating such disorder orcondition, and a pharmaceutically acceptable carrier.

The invention is also directed to a method of treatment of a disorder orcondition selected from the group consisting of the disorders orconditions listed in the preceding paragraph (e.g. human Africantrypanosomiasis, Chagas disease), the method comprising administering tosaid mammal in need of such treatment an amount of a compound of formulaI as described above that is effective in treating such disorder orcondition.

The invention also relates to the use of a compound of the formula I, ora pharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of a disorder or condition, the treatmentof which can be effected or facilitated by administration of aneffective amount of the medicament to a mammal, including a human, inneed of such treatment.

Preferred embodiments of the present invention include the compounds offormula I in which:

(A) R1 and R2 are independently methyl;

-   -   X₁ is C(═NR5)-NR6R7 (formula II); and    -   n is one.

(B) R1 and R2 are independently methyl;

-   -   X₁ is a heteroaryl ring as previously defined; and    -   n is one.

The most preferred embodiment of the present invention includes thecompounds of formula I in which:

-   -   R1 and R2 are methyl;    -   R3 is hydrogen;    -   X₁ is a heteroaryl ring as previously defined;    -   X₂ is 4-fluoro; and    -   n is one.

Preferred compounds of formula I in accordance with the presentinvention include the following:

-   1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboximidamide;-   1-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl]-1-(morpholin-4-yl)methanimine;    and-   1-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl]-1-(pyrrolidin-1-yl)methanimine.

Other preferred compounds of the general formula include the following:

-   N-(4-chlorobenzyl)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboximidamide;-   N-(3,4-dichlorobenzyl)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboximidamide;-   1-[1-[3-(dimethylamino)propyl]-1-(4-chlorophenyl)-1,3-dihydro-2-benzofuran-5-yl]-1-(morpholin-4-yl)methanimine;-   1-[1-[3-(dimethylamino)propyl]-1-phenyl-1,3-dihydro-2-benzofuran-5-yl]-1-(morpholin-4-yl)methanimine;-   2-(1-[3-aminopropyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole;-   2-(1-[3-(methylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole;-   2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1,3-thiazole;-   2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1,3-oxazole;-   4-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1,3-thiazole;-   2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1,3-thiazole;-   3-(1-[3-dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1,2-isothiazole;-   4-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-2-methyl-1H-imidazole;-   5-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-2,4-dimethyl-1H-imidazole;-   2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-1,3,4-triazole;-   2-(1-[3-(dimethylamino)ethyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole;-   2-(1-[3-(dimethylamino)butyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole;-   2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-4-methyl-1H-imidazole;-   5-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-tetrazole;-   1-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-5-methyl-2H-tetrazole;-   3-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1,2,4-thiadiazole;-   3-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1,2,4-oxadiazole;-   1-methyl-2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole.-   4-methyl-2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole.-   2(S)-2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole.-   2(R)-2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole.-   2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-benzimidazole;-   4,5-dimethyl-2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole;-   2-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl]-1,2,3,4-tetrahydro-1H-isoquinolin-2-yl)methanimine;-   2-(1-[3-dimethylaminopropyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl})-1,3-pyrimidine;-   3-(1-[3-dimethylaminopropyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl})-1,2,4-triazine;-   2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl)-1H-4,5-dihydro-imidazole;-   2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl)-4,5,6,7-tetrahydro-1H-1,3-diazepine;    and-   2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl)-1,4,5,6-tetrahydro-pyrimidine.

The most preferred compounds of the invention include:

-   N-benzyl-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboximid-amide;    and-   2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole.

A preferred use for compounds of formula I is in the treatment of humanAfrican trypanosomiasis (HAT). Other preferred uses for the compounds offormula I are in the treatment of Chagas disease, and in the treatmentof Leishmaniasis.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula I may be prepared as described in the followingreaction schemes and discussions. Unless otherwise indicated, X₁, X₂,R1, R2, R3, R4, R5, R6, R7, R8 and R9, and structural formulae II, III,IV, VI, VIIa, VIIb, VIII, IX in the reaction schemes and discussion thatfollow are as defined above.

According to Scheme 1, compounds of the general formula III may beconverted to an imino-ether (i.e., imidate) of the general formula IV,and next converted to an amidine of the general formula V using theappropriate primary or secondary amine HNR6R7. One efficient method forthis process is via a Pinner reaction, which involves treatment of thenitrile of formula III with an anhydrous acid, preferably hydrochloricacid, and a low molecular weight alcohol R₈OH such as methanol orethanol, preferably ethanol, at a temperature in the range from about 0°C. to about the boiling point of the alcohol used, preferably at about80° C. for ethanol, and at a pressure of about one to three atmospheres,preferably at atmospheric pressure, to generate the intermediateimino-ether IV. The crude intermediate IV can then be reacted with anappropriate amine of the general formula HNR6R7 present in a ratio of0.5 to 5 equivalents, preferably in a ratio of 1 to 3 equivalents, toproduce the amidine compounds of general formula V (i.e., generalformula I where X₁ is —C(NR5)-NR6R7, i.e., formula II). This process isdescribed in a number of organic syntheses texts, including Jie Jack Li,Name Reactions: A Collection of Detailed Mechanisms and SyntheticApplications (4^(th) Ed.), pp. 438-9, Springer-Verlag, New York, 2009).Additional examples of the Pinner reaction and modifications can befound in Patai, The Chemistry of Amidines and Imidates, Wiley, New York,1975, pp. 385-489. A useful review is by R. Roger and D. Neilson,Chemical Reviews, 1961, 61(2), 179-211.

The starting materials for this process, compounds of the generalformula III, are available using procedures described in the chemicaland patent literature. For example, the compound of formula III, whereinn=1, R1=CH3, R2=CH3, R3=H, X₂ is 4-fluoro and the CN group is attachedto the 5-position of the benzofuran ring has been commercially availableas the antidepressant citalopram (in racemic form) and as theantidepressant escitalopram (as the single, (S)-isomer). Procedures forthe syntheses of these compounds are also readily available in theliterature (e.g., see M. Pitts, Tetrahedron, 2006, 62, 4705-4708; N.Periyandi, et al, PCT Int. Appl., (2006), WO-2006021971; T. Ikemoto andY. Watanabe, PCT Int. Appl., (2005), WO-2005082842; H. Ahmadian and H.Petersen, PCT Int. Appl., (2003), WO-2003051861; H. Petersen, PCT Int.Appl. (2001), WO-2001068631; L. Dall'Asta, et al, PCT Int. Appl.,(2000), WO-2000023431).

Alternatively, the imino-ether of general formula IV may be isolated,e.g. as a hydrochloride salt, which may be converted to the freeimino-ether by treatment with a weak base such as sodium bicarbonate, orpurified and subsequently reacted with the appropriate amine of generalformula HNR6R7 to generate the desired product of general formula V.

In some cases, it may also be desirable to convert the nitrile group ofthe compound of formula II directly into the amidine group present inthe compound of formula V (i.e., compound of formula I wherein X₁ is—C(═NR₅)—NR₆R₇). For example, see G. Rousselet, et al, TetrahedronLetters, 1993, 34(40), 6395-6398, and R. Garigipati, TetrahedronLetters, 1990, 31(4), 1969-1972.

According to Scheme 2, a compound of the general formula III, may beconverted directly into an amidine of general formula V using an excessof ammonia under conditions normally employed in the Pinner reaction(see above). These simple amidines of general formula VI can then beconverted to the desired compounds of general formula V (i.e., generalformula I wherein X₁ is a heterocyclic ring, including imidazole).Procedures for this conversion may be found in the chemical literatureand are familiar to one skilled in the art of organic synthesis. Forexample, conversion of intermediate VI, wherein R1 and R2 are methyl, R3is hydrogen, n equals 1 and X₂ is 4-fluoro, can be accomplished using anamino-acetal, followed by ring closure to produce the heterocyclicimidazole ring (e.g., see R. Frutos, et al, Tetrahedron Letters, 2005,46(48), 8369-8372). Other heterocyclic ring systems that can be preparedin this manner include, for example, benzimidazolyl and 1,3-pyrimidinyl.

In another embodiment, the nitrile compound of formula III can bereacted with e.g., sodium azide to directly generate a tetrazolederivative of general formula I, wherein X₁ is:

and R9 is H or C₁-C₃ alkyl (see, for example, B. Das, et al, Synlett,2010, 391-394; J. Roh, et al, Synthesis, 2009, 2175-2178; D. Cantillo,et al, Journal of the American Chemical Society, 2011, 133, 4465-4475;W.-K. Su, European Journal of Organic Chemistry, 2006, 2723-2726.

In another embodiment, an intermediate of the general formula VIII(wherein X₃ is Cl, Br, I) can be converted into a compound of thegeneral formula IX (i.e., general formula I, wherein X₁ is a heteroarylgroup, using one or more of a variety of methods described in thechemical literature. This can be accomplished via a process referred toas a Suzuki (or Suzuki-Miyaura) coupling reaction (e.g., see K. Wong, etal, Journal of Organic Chemistry, 2002, 67(3), 1041-1044). The reactiontypically employs a palladium catalyst to couple an aryl halide with anaryl, or heteroaryl, boronic acid or boronate ester. Examples of thisreaction can be found in, for example, L. Wang, et al, European Journalof Organic Chemistry, 2012, (3), 595-603; M. Li, et al, TetrahedronLetters, 2009, 50(13), 1478-1481; J. C. W. Evans, et al, OrganicSynthesis, 1938, 18. Modifications to this coupling process include theuse of other metals, such as magnesium (for the preparation of1,2,3-triazines—see, A. Ohsawa, et al, Journal of the Chemical Society,Chemical Communications, 1985, (20), 1370); cesium and copper (I) (seeH. Yang, et al, Letters in Organic Chemistry, 2011, 8(5), 325-331; C.Cao, et al, Synthetic Communications, 2012, 42(2), 279-284) andmicrowave conditions (see H. Huang, Journal of Combinatorial Chemistry,2008, 10(5), 617-619). A modification of the Ullmann reaction to preparesubstituted 1,2,4-triazoles has also been described (see P. Suresh, etal, Journal of Organic Chemistry, 2008, 73(22), 9121-9124).

The starting materials for this process, compounds of the generalformula VIII, wherein X₃ is, e.g., chlorine, bromine or iodine, aredescribed in the chemical literature, or may be commercially available(e.g., see J. Eildal, et al, Journal of Medicinal Chemistry, 2008, 51,3045). The aryl, or heteroaryl, boronic acids or esters may be obtainedfrom commercial sources (e.g., Sigma-Aldrich Chemical, St. Louis, Mo.),or prepared as described in the chemical literature (e.g., see P. Zhang,et al, Journal of Medicinal Chemistry, 2010, 53, 6112-6121; P. Bartlett,et al, Chemical Reviews, 1997, 97, 1281; R. Batey, et al, Journal of theAmerican Chemical Society, 1999, 121, 5075; J. Bird, et al, Journal ofMedicinal Chemistry, 1994, 37, 158).

Where cis- and trans-isomers are possible for an embodiment of theinventive compounds of formula I, both cis- and trans-isomers (i.e.,diastereomers) are within the scope of this invention. Similarly, whenR- and S-, or (+)- and (−)-, or d- and l-isomers (i.e., enantiomers) arepossible for an embodiment of the inventive compounds of formula I, eachand every one of said isomers are within the scope of this invention.

The term “alkyl” refers to straight or branched chains of carbon atoms.Exemplary alkyl groups are C₃-C₁₀ alkyl groups which include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl andthe like, including all regioisomeric forms thereof, and straight andbranched chain forms thereof. The term “alkyl” is also used to denotestraight or branched chains of carbon atoms having one or morecarbon-carbon double bonds, such as vinyl, allyl, butenyl and the like,as well as straight and branched chains of carbon atoms having one ormore carbon-carbon triple bonds, such as ethynyl, propargyl, butynyl,and the like.

The term “aryl” denotes a cyclic, aromatic hydrocarbon. Examples includephenyl, naphthyl, anthracenyl, phenanthracenyl, and the like.

The terms “alkoxy” and “aryloxy” denote “O-alkyl” and “O-aryl”,respectively. The term “cycloalkyl” denotes a cyclic group of carbonatoms, where the ring formed by the carbon atoms may be saturated or maycomprise one or more carbon double bonds in the ring. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and the like as well as cyclopentenyl,cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like. As usedherein, the term “cycloalkyl” is also intended to denote a cyclic groupcomprising at least two fused rings, such as adamantyl,decahydronaphthalinyl, norbornanyl, where the cyclic group may also haveone or more carbon-carbon double bonds in one or more rings, such as inbicyclo(4.3.0)nona-3,6(1)-dienyl, dicyclopentadienyl,1,2,3,4-tetrahydronaphthalinyl(tetralinyl), indenyl, and the like.

The term “one or more substituents” as used herein, refers to a numberof substituents that equals from one to the maximum number ofsubstituents possible based on the number of available bonding sites.

The terms “halo” and “halogen”, as used herein, unless otherwiseindicated, include chloro, fluoro, bromo and iodo.

The term “heteroaryl” denotes a monocyclic or bicyclic aromatic groupwherein one or more carbon atoms are replaced with heteroatoms selectedfrom the group consisting of nitrogen, oxygen, and sulfur. If theheteroaryl group contains more than one heteroatom, the heteroatoms maybe the same or different. Preferred heteroaryl groups are five- tofourteen-member rings that contain from one to three heteroatomsindependently selected from oxygen, nitrogen, and sulfur. Examples ofpreferred heteroaryl groups include benzo[b]thienyl, chromenyl, furyl,imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuranyl,isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, napthylidinyl,oxadiazolyl, oxazinyl, oxazolyl, phthalazinyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolyl, pyridazinyl and pyridinyl.

The term “treating”, as used herein, refers to reversing, alleviating,inhibiting the progress of, or preventing the disorder or condition towhich such term applies, or preventing one or more symptoms of suchdisorder or condition. The term “treatment”, as used herein, refers tothe act of treating, as “treating” is defined immediately above.

The compounds of formula I of the present invention may also containfunctional groups or heterocyclic ring systems that may exist in one ormore tautomeric forms. The present invention includes within its scopeall such tautomeric forms, including mixtures of such forms.

The compounds of the present invention may have optical centers andtherefore may occur in different enantiomeric configurations. Formula I,as depicted above, includes all enantiomers, diastereomers, and otherstereoisomers of the compounds depicted in structural formula I, as wellas racemic and other mixtures thereof. Individual isomers can beobtained by known methods, such as optical resolution, opticallyselective reaction, or chromatographic separation in the preparation ofthe final product or its intermediate.

The compounds of formula I may also exist in the form of cis- ortrans-isomers with respect to configuration on the furan ring of formulaI. Such cis- and trans-isomers are also considered to be within thescope of the present invention,

The present invention also includes isotopically labeled compounds,which are identical to those recited in formula I, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe present invention include isotopes of hydrogen, carbon, nitrogen,oxygen, sulfur, phosphorus, fluorine, and chlorine, such as ²H, ³H, ¹¹C,¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁷O, ¹⁸O, ³⁵S, ³¹P, ³²P, ³¹P, ¹⁸F and ³⁷Cl,respectively. Certain isotopically labeled compounds of the presentinvention, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and hence may be preferred insome circumstances. Isotopically labeled compounds of formula I of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the Schemes and/or the examples andPreparations below, by substituting a readily available isotopicallylabeled reagent for a non-isotopically labeled reagent.

Compounds of the present invention, prodrugs thereof, andpharmaceutically acceptable salts of said compounds, or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention.

A “unit dosage form” as used herein is any form that contains a unitdose of the compound of formula I. A unit dosage form may be, forexample, in the form of a tablet or a capsule. The unit dosage form mayalso be in liquid form, such as a solution or suspension.

The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the present invention may beformulated for oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or in a formsuitable for administration by inhalation or insufflations.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents(e.g., pre-gelatinized maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose), fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc, or silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulfate). The tabletsmay be coated by methods well known in the art. Liquid preparations fororal administration may take the form of, for example, solutions, syrupsor suspensions, or they may be presented as a dry product forconstitution with water or other suitable vehicle before use. Suchliquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters or ethyl alcohol); and preservatives(e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

The active compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampoules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispensing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

The active compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration by inhalation, the active compounds of theinvention are conveniently delivered in the form of a solution orsuspension from a pump spray container that is squeezed or pumped by thepatient or as an aerosol spray presentation from a pressurized containeror a nebulizer, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrachloroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insulator may be formulated containing a powder mixof a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of the active compounds of the invention for oral,parenteral or buccal administration to the average adult human for thetreatment of the conditions referred to above (e.g., HAT) is from about0.1 mg/kg to about 100 mg/kg of the active ingredient per unit dosewhich could be administered, for example, one to four times per day.Toxicity concerns at the higher level may restrict intravenous (i.v.)dosages to a lower level, such as up to about 10 mg/kg. A dose of about0.1 mg/kg to about 100 mg/kg may be employed for oral (p.o.)administration. Typically, a dosage from about 0.1 mg/kg to about 10mg/kg may be employed for intramuscular (i.m.) injection. Preferreddosages are in the 1.0 mg/kg to about 100 mg/kg range, and morepreferably in the 5 mg/kg to about 50 mg/kg range for i.v. or p.o.administration. The duration of the treatment is usually once per dayfor a period of three days to three weeks, or until the condition isessentially controlled. Lower doses given less frequently can be usedprophylactically to prevent or reduce the incidence of recurrence of theinfection.

Aerosol formulations for treatment of the conditions referred to above(e.g., HAT) in the average human are preferably arranged such that eachmetered dose or “puff” of aerosol contains 0.1 micrograms to 100micrograms of the compound of the invention. The overall daily dose withan aerosol will be within the range of 0.1 mg/kg to about 100 mg/kg, andpreferably in the range of 1.0 mg/kg to about 25 mg/kg. Administrationmay be several times daily, for example 2, 3, 4 or 8 times, giving forexample 1, 2 or 3 doses each time.

Examples of the disorders or conditions which may be treated by acompound, composition and method of this invention include: humanAfrican trypanosomiasis (HAT), Chagas disease, Leishmaniasis,giardiasis, pneumocystis carinii pneumonia or malaria.

As an example, the mammal in need of treatment or prevention may be ahuman. As another example, the mammal in need of treatment or preventionmay be a mammal other than a human.

In so far as the compounds of formula I of this invention are basiccompounds, they are capable of forming a variety of different salts withvarious inorganic and organic acids. Although such salts must bepharmaceutically acceptable for administration to animals, includinghumans, it is often desirable in practice to initially isolate the basecompound from the reaction mixture as a pharmaceutically unacceptablesalt, then isolate the base by treatment of the salt with an alkalinereagent and finally convert the isolated free base compound to apharmaceutically acceptable acid addition salt.

The acids which are used to prepare the pharmaceutically acceptable acidsalts of the active compound used in formulating the pharmaceuticalcomposition of this invention that are basic in nature are those whichform non-toxic acid addition salts, e.g., salts containingpharmacologically acceptable anions. Non-limiting examples of the saltsinclude the acetate, benzoate, beta-hydroxybutyrate, bisulfate,bisulfite, bromide, butyne-1,4-dioate, caproate, chloride,chlorobenzoate, citrate, dihydrogen phosphate, dinitrobenzoate,fumarate, glycollate, heptanoate, hexyne-1,6-dioate, hydroxybenzoate,iodide, lactate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methoxybenzoate, monohydrogen phosphate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, oxalate,phenylbutyrate, phenylpropionate, phosphate, phthalate, phenylacetate,propanesulfonate, propiolate, propionate, pyrophosphate, pyrosulfate,sebacate, suberate, succinate, sulfate, sulfite, sulfonate, tartrate,xylenesulfonate, acid phosphate, acid citrate, bitartrate, succinate,gluconate, saccharate, nitrate, methanesulfonate, and pamoate {i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Also included within the scope of this invention are solvates andhydrates of compounds of formula I and their pharmaceutically acceptablesalts. The present invention includes within its scope all possiblestoichiometric and non-stoichiometric forms.

In the examples that follow, the abbreviations used are intended to havethe following, general meaning:

bm: broad multiplet (NMR)

bs: broad singlet (NMR)

d: doublet (NMR)

dd: doublet of doublets (NMR)

d.e.: diatomaceous earth, filtering agent

calcd.: calculated value

equiv: equivalent

J: coupling constant (NMR)

HPLC: high pressure liquid chromatography

m: multiplet (NMR)

min: minute(s)

m/z: mass to charge ratio (mass spectroscopy)

obsd: observed value

Rf: retention factor (chromatography)

RT: retention time (chromatography)

rt: room temperature (typically 25° C.)

s: singlet (NMR)

t: triplet (NMR),

T: temperature

tlc: thin layer chromatography

TFA: trifluoroacetic acid

THF: tetrahydrofuran

Solvents were purchased and used without purification. Yields werecalculated for material judged homogeneous by thin layer chromatographyand NMR. Thin layer chromatography was performed on Kieselgel plateseluting with the indicated solvents, visualized by using a 254 nm UVlamp, and stained with either an aqueous KMnO₄ solution or an ethanolicsolution of 12-molybdophosphoric acid.

Nuclear Magnetic Resonance (NMR) spectra were acquired on a 400 MHz NMRSpectrometer. Chemical shifts for proton (i.e., ¹H) NMR spectra arereported in parts per million (ppm) relative to the singlet of CDCl₃ at7.24 ppm.

Conditions for High Pressure Liquid Chromatography—Mass Spectrometry(HPLC-MS) analysis:

-   -   Column: Zorbax RRHD Eclipse Plus (Agilent) C₁₈, 1.9 micron, 50        mm×2.1 mm

Eluent I.

A: Acetonitrile-H₂O=5:95, 20 mM HCOONH₄/NH₄OH buffer, pH 7.4

B: Acetonitrile-H₂O=80:20, 20 mM HCOONH₄/NH₄OH buffer, pH 7.4

Eluent II.

A: H₂O with 0.1% TFA, pH 2.2

B: Acetonitrile with 0.1% TFA, pH 2.2

-   -   Gradient program: adjusted according to the compound properties;        typically, start: 0% B to 100% B in 1 minute, 0.8 minute        isocratic B.    -   Column Temp.: 40° C.    -   Flow Rate: 0.6 mL/min    -   Sample Conc.: ca. 1 mg/mL    -   Sample Solvent: Acetonitrile    -   Injection: 0.5 μL    -   Detection wavelength: 220 nm        Mass Spectrum (MS) conditions:    -   Measured Mass Range: 100-750 Daltons    -   Scan Time: 0.2 s    -   Ion mode: ES±    -   Cone Voltage: 20 V    -   Capillary Voltage: 3 V    -   Source temp.: 140° C.    -   Desolvation temp.: 450° C.    -   Desolvation gas: 450 L/h    -   Cone gas: 60 L/h

Example 1

1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboximidamide

A mixture of1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrilehydrobromide (citalopram hydrobromide, 300 mg, 1.0 equiv), copper(II)chloride (1.5 equiv) and ammonia (2.8 equiv) in ethanol (6 mL) washeated at 80° C. for 48 h. The mixture was cooled to room temperatureand concentrated to dryness to give crude product (M/Z 342 [M⁺+H]). Thismaterial was purified by re-suspending the crude product in freshethanol, filtration to remove insoluble material and slow evaporationunder N2 to give the title product, 90 mg (23%) of a pale yellow powder.

LC: 97%;

MS: calcd. for C₂₀H₂₄FN₃O: 341.2; obsd. 342 (M⁺+H).

The following compounds 2 through 8 were also prepared using the generalprocedure as described for the title compound of Example 1.

Example 2

N-ethyl-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboximidamide

Using 250 mg of1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrilehydrobromide (citalopram HBr, 1.0 equiv) and ethylamine (1.3 equiv)gave, after heating at 80° C. for 15 h, the title product (65 mg, 19%yield) as a white solid.

LC: 91%;

MS: calcd. for C₂₂H₂₈FN₃O: 369.2; obsd. 370 (M⁺+H).

Example 3

N,N-dimethyl-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboximidamide

Using 300 mg of1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrilehydrobromide (citalopram HBr) and dimethylamine (1.3 equiv) gave, afterheating at 80° C. for 14 h, title product (90 mg, 26% yield) as a lightyellow semisolid.

LC: 99%;

MS: calcd. for C₂₂H₂₈FN₃O: 369.2; obsd. 370 (M⁺+H).

Example 4

N-benzyl-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboximidamide

Using 250 mg of1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrilehydrobromide (citalopram HBr) and benzylamine (1.2 equiv) gave, afterheating at 80° C. for 14 h, title product (72 mg, 19% yield) as a whitesolid.

LC: 97%;

MS: calcd. for C₂₇H₃₀FN₃O: 431.2; obsd. 432 (M⁺+H).

Example 5

1-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl]-1-(morpholin-4-yl)methan-imine

Using 400 mg of1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrilehydrobromide (citalopram HBr) and morpholine (1.5 equiv) gave, afterheating at 80° C. for 28 h, title product (75 mg, 15% yield) as a whitesolid.

LC: 96.9%;

MS: calcd. for C₂₄H₃₀FN₃O₂: 411.2; obsd. 412 (M⁺+H).

Example 6

1-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl]-1-(pyrrolidin-1-yl)methan-imine

Using 100 mg of1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrilehydrobromide (citalopram HBr) and pyrrolidine (1.2 equiv) gave, afterheating at 80° C. for 14 h, title product (58 mg, 40% yield) as a lightyellow solid.

LC: 91%;

MS: calcd. for C₂₄H₃₀FN₃O.2HCl: 395.2; obsd. 396 (M⁺+H). ¹H-NMR(DMSO-d₆, 400 MHz, T=30° C.) δ 1.52 (m, 2H), 1.85 (m, 2H), 2.05 (m, 2H),2.20 (m. 2H), 2.35 (m, 2H), 2.65 (s, 6H), 3.05 (m, 2H), 3.38 (m, 2H),3.53 (m, 2H), 5.22 (q, 2H), 7.18 (m, 2H), 7.60 (m, 4H), 7.75 (d, 1H),8.80 (s, 1H), 9.22 (s, 1H), 10.15 (bs, 1H).

Example 7

2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole

A mixture of1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrilehydrobromide (citalopram HBr, 300 mg, 1.0 equiv) and copper(I) chloride(1.5 equiv) in ethanol (6 mL) was treated with aminoacetaldehydediethylacetal (1.3 equiv) and heated under N₂ at 80 C for 14 hr. Withoutpurification, the mixture containing the intermediate acetal was treatedwith ethanol (8 mL) and 6N HCl (2 mL) at 80 C for 2 hr. The reactionmixture was cooled to room temperature, the solvent removed in vacuo andthe residue purified as in example 1 to produce the title product, 65 mg(12%) as a light yellow solid. LC: 96.1%;

MS: calcd. for C₂₂H₂₄FN₃O: 365.2; obsd. 366 (M⁺+H).

¹H-NMR (DMSO-d₆, 400 MHz, T=30° C.) δ 1.34-1.71 (m, 2H), 2.25 (m, 2H),2.65 (s, 6H), 3.05 (m, 2H), 5.25 (q, 2H), 7.18 (m, 2H), 7.62 (m, 2H),7.75 (m, 2H), 7.85 (m, 1H), 8.05 (m, 1H), 8.12 (m, 1H), 10.0 (bs, 1H),14.9 (bs, 1H).

Determination of Biological Activity T. brucei brucei Assay

The growth inhibition assay for T. brucei brucei was conducted asdescribed previously by Z. B. Mackey et al (Kenny K. H. Ang, JoselineRatnam, Jiri Gut, Jennifer Legac, Elizabeth Hansell, Zachary B. Mackey,Katarzyna M. Skrzypczynska, Anjan Debnath, Juan C. Engel, Philip J.Rosenthal, James H. McKerrow, Michelle R. Arkin, Adam R. Renslo (2011)“Mining a Cathepsin Inhibitor Library for New Antiparasitic Drug Leads”,PLoS Neglected Tropical Diseases, 5(5):e1023). Bloodstream forms of themonomorphic T. brucei brucei clone 427-221a were grown in complete HMI-9medium containing 10% FBS, 10% Serum Plus medium (Sigma Inc., St. Louis,Mo., USA), 50 U/mL penicillin and 50 mg/mL streptomycin (Invitrogen) at37° C. under a humidified atmosphere and 5% CO₂. Inhibitor stocks wereprepared in 100% DMSO and screened at 5 mM for percent inhibition valuesor serially diluted from 25 mM to 0.04 mM in 10% DMSO for IC50determinations. 5 mL of each dilution was added to 95 mL of dilutedparasites (16104 cells per well) in sterile Greiner 96-well flat whiteopaque culture plates such that the final DMSO concentration was 0.5%.The 0% inhibition control wells contained 0.5% DMSO while 100%inhibition control wells contained 50 mM thimerosal (Sigma). Aftercompound addition, plates were incubated for 40 hours at 37° C. At theend of the incubation period, 50 mL of CellTiter-Glo™ reagent (PromegaInc., Madison, Wis., USA) was added to each well and plates were placedon an orbital shaker at room temperature for 2 min to induce lysis.After an additional 10 min of incubation without shaking to stabilizethe signal, the ATP-bioluminescence of each well was determined using anAnalyst HT plate reader (Molecular Devices, Sunnyvale, Calif., USA). Rawvalues were converted to log 10 and percentage inhibition calculatedrelative to the controls. IC50 curve fittings were performed with Prism4 software as above. Pentamidine was used as a comparator in the assay.

DATA Compound Example IC50 (μM) (95% Confidence Intervals) 1 32 (24-41)4  8.8 (5.8-13.4) 5 37 (28-47) 6 24 (20-29) 7  1.4 (1.1-1.9)

What is claimed:
 1. A compound of the formula (I):

or the pharmaceutically acceptable salt(s) thereof, wherein: X₁ is agroup of the general formula:

wherein R5, R6 and R7 are independently defined as H, C₁-C₆ alkyl,C₃-C₇-cycloalkyl, un(substituted) aryl, or heteroaryl; or R5 and R6,taken together with the N—C═N group to which they are attached form a5-10 member cyclic or bicyclic ring, optionally substituted with up totwo additional heteroatoms selected from the group consisting of N, O orS (including, for example, the cyclic or bicyclic ringsdihydro-imidazole and benzimidazole) and optionally substituted with H,C₁-C₆ alkyl or cycloalkyl groups, (un)substituted aryl or heteroarylrings, or oxygen, e.g., sulfoxide or sulfone); or R6 and R7, takentogether with the nitrogen atom to which they are attached form a 5-10member cyclic or bicyclic ring, optionally substituted with up to twoadditional heteroatoms selected from the group consisting of N, O or S(including, for example, the cyclic or bicyclic rings azetidine,pyrrolidine, piperidine, azepine, piperazine, morpholine,thiomorpholine) and optionally substituted with H, C₁-C₆ alkyl orcycloalkyl groups, aryl or heteroaryl rings, or oxygen, e.g., sulfoxideor sulfone); X₂ is H, Cl, or F; R1 and R2 are independently hydrogen ormethyl; R3 is hydrogen; and n is zero, one or two.
 2. The compound ofclaim 1, wherein R1 and R2 are both hydrogen.
 3. The compound of claim1, wherein R3 is hydrogen.
 4. The compound of claim 1, wherein X₂ is4-fluorophenyl.
 5. The compound of claim 1, wherein n is one. 6.(canceled)
 7. The compound of claim 1, wherein X₁ is a group of thegeneral formula:


8. The compound of claim 1, wherein R5 and R6, taken together with theN—C═N group to which they are attached form a 4-7 member cyclic orbicyclic ring optionally substituted with up to two additionalheteroatoms selected from the group consisting of N, O or S (including,for example, the cyclic or bicyclic rings imidazole, oxadiazole,thiadiazole, benzimidazole) and optionally substituted with H, C₁-C₆alkyl or cycloalkyl groups, (un)substituted aryl or heteroaryl rings, oroxygen, e.g., sulfoxide or sulfone).
 9. The compound of claim 1, whereinR6 and R7, taken together with the nitrogen atom to which they areattached form a 4-7 member cyclic or bicyclic ring, optionallysubstituted with up to two additional heteroatoms selected from thegroup consisting of N, O or S (including, for example, the cyclic orbicyclic rings azetidine, pyrrolidine, piperidine, azepine, piperazine,morpholine, thiomorpholine, oxazole, thiazole) and optionallysubstituted with H, C₁-C₆ alkyl or cycloalkyl groups, aryl or heteroarylrings, or oxygen, e.g., sulfoxide or sulfone).
 10. The compound of claim1, wherein R1 is hydrogen, R2 is hydrogen, R3 is hydrogen, n is one, X₂is 4-fluoro.
 11. The compounds of formula I according to claim 1,wherein the compound is selected from:1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboximidamide;N-benzyl-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboximid-amide;1-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl]-1-(morpholin-4-yl)methanimine;and1-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl]-1-(pyrrolidin-1-yl)methanimine.12. The compounds of formula I according to claim 1, wherein thecompound is selected from the group consisting of:N-(4-chlorobenzyl)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboximidamide;N-(3,4-dichlorobenzyl)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboximidamide;1-[1-[3-(dimethylamino)propyl]-1-(4-chlorophenyl)-1,3-dihydro-2-benzofuran-5-yl]-1-(morpholin-4-yl)-methanimine;1-[1-[3-(dimethylamino)propyl]-1-phenyl-1,3-dihydro-2-benzofuran-5-yl]-1-(morpholin-4-yl)-methanimine;2-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl]-1,2,3,4-tetrahydro-1H-isoquinolin-2-yl)methanimine;2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl)-1H-4,5-dihydro-imidazole;2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl)-4,5,6,7-tetrahydro-1H-1,3-diazepine;and2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl)-1,4,5,6-tetrahydro-pyrimidine.13. A pharmaceutical composition for treating a disorder or condition(e.g., human African trypanosomiasis, Chagas disease, Leishmaniasis,malaria) in a mammal, including a human, that may be treated byadministering to a mammal in need of such treatment a compound offormula I as described in claim 1, or a pharmaceutically acceptable saltthereof, that is effective in treating such disorder or condition, and apharmaceutically acceptable carrier.
 14. (canceled)
 15. The use of acompound of the formula I as described in claim 1, or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for thetreatment of a disorder or condition (e.g. human Africantrypanosomiasis, Chagas disease, Leishmaniasis, malaria), the treatmentof which can be effected or facilitated by administration of aneffective amount of the medicament to a mammal, including a human, inneed of such treatment.